Diseases linked to disruption of the transport of copper, such as Wilson's disease, lead to an accumulation of copper in the liver, which is the sole organ capable of excreting it. Thus, although copper is an element that is essential for life, it can, in the free state, induce oxidation reactions of the Fenton type and, consequently, prove extremely toxic. More particularly, Wilson's disease is a genetic disease linked to a deficiency of a copper transporter, leading to an accumulation of copper in various regions of the body (up to 20 times the normal levels), which manifests itself by impairment of the liver and of the nervous system. It leads to a disruption of the physiological concentrations of copper in the individual, which manifests itself by severe neurological and hepatic disorders. Psychological disorders may appear with changes in the character, leading to hyperemotivity with high mood lability, depressive syndromes and psychotic states. Wilson's disease is induced by the mutation of the ATP7B gene, which codes for a transmembrane protein of the ATPase type, involved in the transport of copper, allowing the regulation of the concentration of copper, and its excretion in the bile. If the protein is deficient, the metal then accumulates inside the cells. Impairment of the liver precedes, as a general rule, the neurological impairment by a few years. The neurological or psychiatric signs affect nearly 50% of the patients with Wilson's disease. Magnetic resonance imaging (MRI) shows lesions of several brain structures, even in the absence of any clinical sign and the extent thereof appears to correlate with the degree of advancement of the disease. In extremely serious cases of fulminant hepatitis or in essentially hepatic serious impairments, a liver transplant may be envisaged.
Currently, treatments exist which are aimed at eradicating the toxicity of the copper that has accumulated in the body. These treatments must be followed for life, and must never be interrupted. They are based on chelating drugs which reduce the absorption of copper in the body, or which increase the excretion of this metal. The treatments must be subject to periodic monitoring, so as to detect the appearance of undesirable side effects. The existing treatments use various active ingredients, such as:                D-penicillamine (Pen), which increases urinary excretion of copper (G. J. Brewer, DDT, 2005, 10, pp. 1103-1109). D-penicillamine has a recognized efficacy and forms with copper(I) a Cu(I)-Pen complex which has a stability constant of 1012 (M. Hefter et al., J. C. S., Chem. Commun., 1993, 1704-1706), however it has numerous side effects which tend to cause it to be replaced by other molecules. Moreover, a number of recent articles report a worsening of Wilson's disease with D-penicillamine and suggest restricting its prescription in this indication;        triethylenetetramine (Trien), which is a copper chelator that is often better tolerated than D-penicillamine, and which forms a Cu(II)-Triene complex with copper(II) having a stability constant of 1020 (R. M. Smith et al., 2001, NIST Critically Selected Stability Constants of Metal Complexes Database, NIST Standard Reference Database 46);        the ammonium tetrathiomolybdate (TTM) anion, taken with food, which binds with the copper ions in the digestive tube, thus preventing their absorption;        zinc activates the production of proteins, the metallothioneins, which will bind the copper in the cells of the intestinal wall (enterocytes), preventing the passage of this ion into the blood stream (B. Sarkar, Chem. Rev., 1999, 99, 2535-2544).        
Currently, drugs based on D-penicillamine, whose mechanism of action is still poorly known, are the most widely used. By virtue of its SH functional group, D-penicillamine can:                chelate copper and zinc, but also mercury and lead, and increase their urinary excretion,        reduce the disulfide bridges of certain molecules: collagen, elastic fibers, immunoglobulins, and thus modify their biological activity,        combine with other sulfur-containing molecules, in particular cysteine, forming disulfide bridges.        
It indeed appears that the presence of soft atoms, such as sulfur, allows a more effective chelation of the so-called “soft ion” metal ions such as copper Cu(I) and mercury Hg(II).
Other drugs also exist whose action is comparable to that of D-penicillamine because of the similarity of their pharmacological properties:                pyritinol, which is a symmetrical molecule formed of two parts linked by a disulfide bridge. In the body, pyritinol is cleaved into two molecules, each containing an —SH group. However, pyritinol has been used in the treatment of rheumatoid arthritis with indications and undesirable effects of the same type as those of D-penicillamine,        tiopronin, which is used in the long-term treatment of rheumatoid arthritis and of cystine lithiasis.        
However, the undesirable effects of D-penicillamine and of drugs having a similar mode of action are fairly high in number:                early cutaneo-mucosal and not very serious: erythema, stomatitis,        late cutaneo-mucosal and serious: toxicoderma, pemphigus, dermatomyositis,        hematological: thrombopenia, leukopenia, agranulocytosis, hemolytic anemia, justifying hematological monitoring of the patients treated,        digestive: ageusia,        renal: proteinuria.        
Metals are also considered as therapeutic targets of interest for the diagnosis, prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease, for which the dysregulation of zinc and copper homeostasis plays a critical role. The copper Cu(II) is complexed and reduced to copper Cu(I) by the APP protein and the Aβ peptide, the copper Cu(I) then accumulating in the amyloid plaques with iron and zinc (E. Gaggelli et al., 2006, 106, 1995-2044).
Copper has two stable oxidation states under different conditions: copper Cu(I) having an oxidation state +I, which is stable in a reducing medium, and copper Cu(II) having an oxidation state +II, which is stable in an oxygenated medium. The copper that is present in human cells is mainly copper Cu(I).
Molecules other than D-penicillamine (Pen), may also be used to chelate copper in vivo. They are, for example, 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propanesulfonic acid (DMPS) (O. Andersen, Chem. Rev., 1999, 99, 2683-2710), 2,3-dimercaptopropanol (BAL), triethylenetetramine (Trien), the ammonium tetrathiomolybdate (TTM) anion (G. J. Brewer et al., J. Hepatol., 2005, 42, S13-S21) and ethylenediaminetetraacetic acid (EDTA), which correspond to the following semi-structural formulae:

These compounds are known chelating agents for copper Cu(I) and/or copper Cu(II), which block the intestinal absorption of copper. However, these compounds lead to undesirable side effects, and do not allow the treatment of patients for whom the diseases have been detected at an already advanced stage (non-early detection), and for whom there is a large intracellular accumulation of copper (B. Sarkar, Chem. Rev., 1999, 99, 2535-2534; G. J. Brewer et al., J. Hepatol., 2005, 42, S13-S21). Furthermore, some chelating agents, such as EDTA, are very strong chelating agents, which chelate numerous metal ions, and one of the main disadvantages of which is their lack of selectivity.
The apparent complexation constants of some known chelating agents (R. M. Smith et al., 2001, NIST Critically Selected Stability Constants of Metal Complexes Database, NIST Standard Reference Database 46) are reported in table I below:
TABLE ILog Kappat T = 298 K(at pH = 7.4)EDTATrienPenBALCa(II)7.8———Cu(I)——8.3—Cu(II)16.016.0——Zn(II)13.77.95.8 9.0Cd(II)13.76.67.6—Hg(II)18.720.614.921.2Pb(II)15.26.39.2—Selectivity Cu/Zn2.38.12.5—Selectivity Hg/Zn512.79.112.2
The selectivity between two metals M/M′ corresponds to the selectivity of the ligand for the metal M compared with that for the metal M′, this selectivity being equal to:log(Kapp(M)/Kapp(M′))=log Kapp(M)−log Kapp(M′)
EDTA and Trien are chelating agents for copper Cu(II). EDTA is a very strong hexadentate chelating agent having donor atoms nitrogen and oxygen, one of the main disadvantages of which is the lack of selectivity (it very strongly complexes all the essential and toxic ions cited in table I). Trien, for its part, is a very strong polyamine chelating agent which strongly complexes the metal ions mercury Hg(II) and copper Cu(II), and which exhibits relative selectivity toward the zinc ions Zn(II).
Pen is a chelating agent containing a thiol functional group as well as donor atoms nitrogen and oxygen. The presence of the thiol group makes it possible to achieve a relatively high affinity with the toxic ion Hg(II), while being selective toward the zinc ions Zn(II). However, the selectivity of Pen for the copper ions Cu(I) (compared with the zinc ions Zn(II)) remains low.
BAL is a dithiol chelating agent which has a very high affinity for the mercury ions Hg(II), and probably also for the copper ions Cu(I).
Thus, it appears that the introduction of thiol functional groups promotes the complexing of the soft ions, such as the mercury Hg(II) and copper Cu(I) ions, compared with the other ions.
There is still nevertheless a need today for more selective chelating agents, in particular toward copper, and more particularly intracellular Cu(I), and which are especially less toxic, the side effects of which are thought to be less violent than those of the molecules currently used.